Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer's disease and facilitates APP/BACE1 interactions

Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer’s disease

“…The progression of neurodegenerative diseases related to aging may exacerbate these lipid alterations, thereby inducing profound modifications in raft physicochemical properties (Martı´n et al, 2010;Diaz et al, 2012), that may largely affect protein interactions and trafficking. These evidences have been observed related to, both, AD and PD neuropathology, even at early stages of these diseases (Martı´n et al, 2010;Fabelo et al, 2011Fabelo et al, , 2014. A premature aberrant lipid composition in these microstructures has also been detected in APP/PS1 double-transgenic mice Diaz et al, 2012).…”

“…Furthermore, a subset of BACE1 and c-secretase components also partition into lipid rafts, suggesting that Ab formation occurs in these structures (Ehehalt et al, 2003;Kalvodova et al, 2005). Indeed, recent data have demonstrated that early alterations of membrane microenvironment in lipid rafts from AD brains, promotes the accumulation of BACE1 and increases its interaction with APP (Diaz et al, 2014;Fabelo et al, 2014). Overall, these data point to a dynamic system of Ab production with the participation of different lipid raft modulators.…”

“…corralling into these microstructures enhance production of Ab (Das et al, 2013;Fabelo et al, 2014). On the contrary, non-amyloidogenic processing by a-secretase takes place mainly in non-raft fractions (Ehehalt et al, 2003).…”

The phospholipid composition of the human entorhinal cortex remains relatively stable over 80 years of adult aging

“…DHA has a number of pro-cell survival roles within cell membranes, including the production of anti-inflammatory D-series resolvins and neuroprotectins (Weylandt et al 2012). DHA is known to be severely reduced in many regions of the brain affected by AD pathology (Söderberg et al 1991;Martín et al 2010;Igarashi et al 2011;Cunnane et al 2012;Fabelo et al 2014); however, there are very few studies of this type looking specifically at the changes to the EC. Only a single study has examined the EC for changes in its phospholipids in AD, finding no changes in either total PC, PE or PS (Chan et al 2012).…”

Brain Derived Neurotropic Factor Gene Val66Met Polymorphism in Alzheimer’s Patients in Northern Turkey

“…Moreover, genetic risk factors were also suggested to be important in the development of late-onset familial AD. In particular, inheritance of the ApoEε4 allele is among the most important risk factors for AD [2,3]. When considering the genetic basis of the disease as currently known, it remains unclear if there is a genetic predisposition for AD.…”